Pyridine dicarboxylic acids are useful chemical intermediates for the preparation of a wide variety of final compounds. For example, U.S. Pat. No. 4,518,780 describes cyclization of 2-carbamoyl-3-carboxypyridines, (obtained from pyridine-2,3-dicarboxylic acids) to yield imidazoline herbicides. A variety of such herbicides are known; see for example U.S. Pat. Nos. 4,188,487, 4,404,012, 4,459,408, 4,459,409, 4,638,068, 4,474,962, 4,562,257, 4,608,079, and 4,647,301, among others.
In addition to the traditional sources of pyridine derivatives, biological conversion of aromatic hydrocarbons such as toluene to 2-hydroxymuconic semialdehydes via catechol intermediates has been reported. Upon reaction with ammonia, the 2-hydroxymuconic semialdehydes yield picolinic acid (pyridine-2-carboxylic acid) derivatives. See U.S. Pat. Nos. 4,617,156, 4,654,303, 4,666,841, and 4,673,646.
While various optionally substituted hydrocarbons can be employed as substrates in these processes, they will not afford pyridine-2,3-dicarboxylic acids. Thus with benzoic acid (including that formed by oxidation of toluene), the initially operative enzymes are benzoate 1,2-dioxygenase and 1,2-dihydro-1,2-dihydroxybenzoate dehydrogenase, leading to conversion of the aromatic substrate to a catechol (see U.S. Pat. No. 4,654,303). The catechol in turn is converted to the hydroxymuconic acid semialdehyde derivative by the action of catechol 2,3-oxygenase. As described in the above references, however, the aromatic substrates, while optionally substituted in the meta and para positions, are unsubstituted in the position ortho to the carboxylic acid. In fact catechol 2,3-oxygenase is not operative on an aromatic compound having a carboxylic acid function adjacent to the catechol function, e.g., on a 2,3-dihydroxybenzoic acid type of structure.
Various workers have reported on the enzymatic degradation of 2,3-dihydroxybenzoic acid derivatives through the action of a different enzyme, namely 2,3-dihydroxybenzoate-3,4-dioxygenase (rather than a catechol-2,3-dioxygenase).
Ribbons et al., Arch. Biochem. Biophys., 1970, 138, 557-565, for example, noted formation of a semialdehyde product from a para-substituted 2,3-dihydroxybenzoic acid. Upon treatment with ammonia, however, this gave a picolinic acid product, not a dicarboxylic acid. In light of subsequent work, this would indicate decarboxylation had occurred.
DeFrank et al., J. Bacteriol., 1977, 129, 1365-1374, reported that a mutant of Pseudomonas putida PL-RF-1 which lacked decarboxylase converted 2,3-dihydroxycumate (2,3-dihydroxy-4-isopropylbenzoic acid) into a substance which absorbed at the 345 nm wavelength and which was postulated to be 2-hydroxy-3-carboxy-6-oxo-7-methylocta-2,4-dienoic acid. This decarboxylated spontaneously (or enzymatically in the presence of extracts from a wild-type strain producing active decarboxylate) to yield the isopropyl substituted 2-hydroxymuconic acid semialdehyde (2-hydroxy-6-oxo-7-methylocta-2,4-dienoic acid).
Andreoni et al., Biochem. J.. 1981, 194, 607-610 also observed that when 2,3-dihydroxybenzoic acid was subjected to the action of a Pseudomonas putida extract, carbon dioxide was evolved with 2-hydroxymuconic acid semialdehyde being identified by NMR as the product.
Eaton et al., Arch. Microbiol., 1982, 132, 185-188, studied the action of several strains of Micrococcus on phthalate esters and noted in one case that 2,3-dihydroxybenzoate (presumably following meta oxidation to yield 3,4-dihydroxyphthalate and decarboxylation) also yielded 2-hydroxymuconic acid semialdehyde (absorbing at 375 nm). Since this most likely would occur through the action of a 2,3-dihydroxy-3,4-dioxygenase, Eaton et al. depicted 3-carboxy-2-hydroxymuconic acid semialdehyde as the putative cleavage product. Thus eventual formation of 2-hydroxymuconic acid semialdehyde could only be traced to decarboxylation as, they noted, in fact had been previously reported.
Engesser et al., Arch. Microbiol.. 1988, 149, 198-206, noted the possibility of 2,3-dihydroxy-4-trifluoromethylbenzoic acid being oxidized to the corresponding 3-carboxy-2-hydroxymuconic acid semialdehyde (2-hydroxy-3-carboxy-6-oxo-7,7,7-trifluorohepta-2,4-dienoic acid). They too found, however, that decarboxylation occurred and that the intermediate in fact was the corresponding 2-hydroxymuconic acid semialdehyde 2-hydroxy-6-oxo-7,7,7-trifluorohepta-2,4-dienoic acid, not the 3-carboxy intermediate. Hence reaction of this intermediate with ammonium produced 6-trifluoromethylpicolinic acid with no evidence of 6-trifluoromethylpyridine-2,3-dicarboxylic acid having been formed.
Hence while the possibility of 3-carboxy-2-hydroxymuconic acid semialdehydes being formed from 2,3-dihydroxybenzoate structures under the influence of a 2,3-dihydroxy-3,4-dioxygenase has been postulated, there is at best only circumstantial evidence for its formation and in no case has conversion to pyridine dicarboxylic acids been observed. Quite to the contrary, in each case in which the semialdehyde product has been reacted with ammonia, a picolinic acid (a monocarboxylic acid) rather than a pyridine dicarboxylic acid has been formed.